ABCD syndrome is the acronym for albinism, black lock, cell migration disorder of the neurocytes of the gut and sensorineural deafness. It has been found to be caused by mutation in the endothelin B receptor gene (EDNRB).

ABCD syndrome

Classification and external resources

Facial morphology of Waardenburg syndrome, not type IV

Classification

ABCD syndrome is defined as A- albinism, B- black lock, C- cell migration disorder of the neurocytes of the gut, and D- deafness. It was initially misdiagnosed and later discovered that a homozygous mutation in the EDNRB gene causes ABCD syndrome. This helped scientists discover that it is the same as type IV Waardenburg syndrome, also known as Shah-Waardenburg Syndrome.

Characteristics

In the beginning, medical officials defined ABCD syndrome by the four key characteristics of the syndrome. In the first case study of the Kurdish girl, researches described her as having “albinism and a black lock at the right temporo-occiptital region along Blaschko lines, her eyelashes and brows were white, the irises in her eyes appeared to be blue, she had spots of retinal depigmentation, and she did not react to noise” [1] The A in this syndrome is for albinism which is interesting in this diagnosis because the skin of an affected individual is albino pale besides the brown patches of mispigmented skin. The B of ABCD is described and seen in clinical pictures of the infants as “black locks” that are thick patches of black hair located above the ears and form a half circle reaching to the other ear to make a crest shape. As identified in this first case study and stated in a dictionary of dermatologic syndromes, ABCD syndrome has many notable features, including “snow white hair in patches, distinct black locks of hair, skin white except brown macules, deafness, irides gray to blue, nystagmus, photophobia, poor visual activity, normal melanocytes in pigmented hair and skin, and absent melanocytes in areas of leukoderma” [2]. Individuals have the blue/gray irises typical of people affected by blindness. The C of ABCD syndrome is what distinguishes this genetic disorder from BADS and it involves cell migration disorder of the neurocytes of the gut. The additional characteristic in ABCD occurs when nerve cells do not function correctly in the gut, which results in aganglionosis - the intestines’ failure to move food along the digestive tract. D of ABCD is deafness or being unresponsive to noise due to very low quality of hearing, which was reported in every case of ABCD syndrome. The characteristics of ABCD syndrome are clearly evident in an inflicted individual.

No longer considered a separate syndrome, ABCD syndrome is today considered to be a variation of Shah-Waardenburg type IV. P.J. Waardenburg syndrome (WS) is described as “the combination of sensorinerual hearing loss, hypopigmentation of skin and hair, and pigmentary disturbances of the irides” [3]. Hearing loss and deafness, skin mispigmentation and albinism, and pigmentary changes in irises are the similarities between WS and ABCD. According to the dictionary of dermatologic syndromes, Waardenburg syndrome has many notable features, including “depigmentaion of hair and skin - white forelock and prematuring graying of hair, confluent thick eyebrows, heterochromic irides or hypopigmentation of iris, laterally displacy inner canthi, congenital sensorinerual deafness, broad nasal root, autosomal dominant disorder, and other associated findings, including black forelocks” [2].

Causes

Researchers in the past 20 years have determined that a gene mutation, specifically a homozygous mutation in the EDNRB gene, is the cause of ABCD syndrome. The advancement of technology led to new DNA material testing methods and this discovery changed the view of ABCD syndrome completely. A homozygous mutation means that there was an identical mutation on both the maternal and paternal genes. The identifying clinical report stated the test was done by scanning the Kurdish family for mutations in the EDNRB gene and the EDN3 gene by using a test called denaturing gradient gel electrophoresis. The electrophoresis test takes advantage of electrical currents and differences in melting points of fragments of DNA or RNA to move them based on their molecular weight; the differences in mobility of the fragments then can be analyzed to determine different sequences and to detect individual alleles. Different nucleotides in DNA are codes for certain proteins, which are formed by different patterns of the base pairs adenine, thymine, guanine, and cytosine. The combination of adenine and thymine and guanine and cytosine align on the double strands of DNA. The test results found “an aberrant DGGE pattern of exon 3 of the EDNRB gene. The mutation was determined to be a homozygous C to T base pair transition at the amino acid level, causing a premature stop in gene translation” [3]. This specialized testing enables geneticists to recognize the gene mutation that is the cause of ABCD syndrome.

New findings introduced an important break in the beliefs about ABCD syndrome because the endotherlin B gene is a gene involved in Shah-Waardenburg syndrome. The endothelin receptor B produces Waardenburg syndrome type IV [4]. Researchers began discussing the possibility that ABCD syndrome was in fact not a syndrome - rather it was a type of another syndrome known as Waardenburg. Discovering that the same gene is involved in both ABCD syndrome and Waardenburg syndrome is important because researchers can now look further into ways to fix this crucial gene that causes so many abnormalities on the inside and the outside of individuals.

Screening

Screening generally only takes place among those displaying several of the symptoms of ABCD, but a study on a large group of institutionalized deaf people in Columbia revealed that 5.38% of them were Waardenburg patients. Because of its rarity, none of the patients were diagnosed with ABCD (Waardenburg Type IV). Nothing can be done to prevent the disease.

Diagnosis

The occurrence of WS has been reported to be one in 45,000 in Europe. The diagnosis can be made prenatally by ultrasound due to the phenotype displaying pigmentary disturbances, facial abnormalities, and other developmental defects [5]. After birth, the diagnosis is initially made symptomatically, and can be confirmed through genetic testing. If the diagnosis is not made early enough, complications can arise from the Hirschsprungs.

Treatment

Treatment for the disease itself is nonexistent, but options for most of the individual symptoms do exist. For example, one suffering from hearing loss would be given hearing aids, and those with Hirschsprung’s disorder can be treated with a colostomy.

Prognosis

If the Hirschsprung’s disease is treated in time, ABCD sufferers live otherwise healthy lives. If it is not found soon enough, death often occurs in infancy. For those suffering hearing loss, it is generally regressive and the damage to hearing increases over time. Digestive problems from the colostomy and reattachment may exist, but in most cases can be treated with laxatives. The only other debilitating symptom is hearing loss, which is usually degenerative and can only be treated with surgery or hearing aids.

History

Dutch ophthalmologist, Petrus Johannes Waardenburg (1886–1979), brought about the idea of Waardenburg syndrome when he examined two patients—deaf twins.[6] Waardenburg decided to define the syndrome with the six major symptoms that patients most commonly had. Firstly, he defined, “lateral displacement of the medial canthi combined with dystopia of the lacrimal punctum and blepharophimosis” referring to those people with broader and more flat nasal bridge, which in turn leads to folds in the skin that cover the inner corners of the eye.[6] Secondly, people who are born with a “prominent broad nasal root,” have a widened area between the eyes, causing them to have a more flat and wider face, along with eyes further apart than normal.[6] Thirdly, “hypertrichosis of the medial part of the eyebrows” is present, meaning excessive hair growth in the patients’ eyebrow region, most likely leading to a unibrow.[6] The fourth symptom, “white forelock,” was commonly seen as depigmented strands of hair, fifth “heterochromia iridis,” indicates that the patient had two different colored eyes, or two different colors in the same eyes, and finally, “deaf-mutism” classifying that people with the disorder are both deaf and mute.[6]

When scientists further investigated the syndrome, they realized that patients exhibited a wider range of symptoms of this disease in different combinations. This helped them distinguish different forms of Waardenburg syndrome. Their evaluation consisted of specifying Waardenburg syndrome type I (WS1), type II (WS2), type III (WS3), and type IV (WS4).

In 1995, a case study was performed of a Kurdish family. Scientists completed a molecular analysis with DNA strands of the patients diagnosed with ABCD syndrome. Their task was to scan the sequences to find a mutation in the EDNRB gene, one of the most important protein-coding genes. When they completed the scan they “found a homozygous C to T transition resulting, at the amino acid level, in a premature stop codon” [3]. Then, they went back and defined that Shah-Waardenburg syndrome consisted majorly of “mutations in the ENDRB or END3 gene,” along “with [some] SOX10 mutations” [3]. Therefore, the researchers confirmed that ABCD syndrome was a form of Shah-Waardenburg syndrome. The genetic tests that they performed on the patients DNA helped in identifying the appropriate diagnosis.

Later, Whitkop, another scientists, in 2002, examined patients born with white hair, some black locks, and depigmented skin, hence, he diagnosed them as having black lock albinism deafness syndrome also known as BADS [1]. Those who were closely working with this case suggested that it was an autoimmune disorder rather than a genetic defect. However, soon after, they had a patient come in who was one of fourteen children of Kurdish parents. The pedigree they examined revealed autosomal-recessive inheritance which led to cell migration of the neurocytes in the gut, and therefore, they redefined the syndrome as ABCD Syndrome” [1]. This revealed “a homozygous nonsense mutation in the EDNRB gene” meaning that ABCD Syndrome was not a separate entity, but rather the same as Shah-Waardenburg syndrome [3].

Aase syndrome or Aase-Smith syndrome is a rare inherited disorder characterized by anemia with some joint and skeletal deformities. Aase syndrome is thought to be an autosomal recessive inherited disorder.[1] The genetic basis of the disease is not known. The anemia is caused by underdevelopment of the bone marrow, which is where blood cells are formed.

It is named after the American paediatricians Jon Morton Aase and David Weyhe Smith, who characterized it in 1968.[2]

Symptoms

Inability to fully extend the joints from birth (congenital contractures)

Cleft palate

Deformed ears

Droopy eyelids

Signs and tests

A CBC (complete blood count) will show anemia and a decrease in the white blood cell count.

An echocardiogram may reveal heart defects (ventricular septal defect is most common).

X-rays will show skeletal abnormalities as described above.

A bone marrow biopsy may be performed.

Treatment

Frequent blood transfusions are given in the first year of life to treat anemia. Prednisone may be given, although this should be avoided in infancy because of side effects on growth and brain development. A bone marrow transplant may be necessary if other treatment fails.

Prognosis

Anemia usually resolves over the years.

Complications

Complications related to anemia include weakness, fatigue, and decreased oxygenation of the blood.

If a heart defect exists, it may cause multiple complications (depending on the specific defect).

Severe cases have been associated with still birth or early death.

Prevention

As with most genetic diseases there is no way to prevent the entire disease. With prompt recognition and treatment of infections in childhood, the complications of low white blood cell counts may be limited.

Aarskog–Scott syndrome is an inherited disease characterized by short stature, facial abnormalities, skeletal and genital anomalies.

The Aarskog–Scott syndrome (AAS) is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and faciogenital dysplasia.

Signs and symptoms

The Aarskog–Scott syndrome is a disorder with short stature, hypertelorism, downslanting palpebral fissures, anteverted nostrils, joint laxity, shawl scrotum, and mental retardation. The physical phenotype varies with age and postpuberal males may have only minor remnant manifestations of the prepuberal phenotype.

Growth

mild to moderate short stature evident by 1–3 years of age

delayed adolescent growth spurt

Performance

slight (dull normal) to moderate mental deficiency

hyperactivity and attention deficit

social performance usually good

Face

rounded face

widow's peak hairline

wide-set eyes (hypertelorism)

droopy eyelids (blepharoptosis)

downslanting eye slits (palpebral fissures)

small nose with nostrils tipped forward (anteverted)

underdeveloped mid-portion of the face (maxilla)

wide groove above the upper lip (broad philtrum)

crease below the lower lip

delayed eruption of teeth

top portion (upper helix) of the ear folded over slightly

Hands and feet

small, broad hands and feet

short fingers and toes (brachydactyly)

in-curving of the 5th finger (clinodactyly)

mild interdigital webbing, between fingers as well as toes

single transverse "simian crease" in palm

broad thumbs and big toes

Neck

short neck

webbing of sides of the neck

Chest

mild pectus excavatum (sunken chest)

Abdomen

protruding navel

inguinal hernias

Genitalia

Shawl Scrotum

undescended testicles

Genetics

X-linked recessive inheritance.

Aarskog–Scott syndrome is transmitted in an X-linked recessive manner. The sons of female carriers are at 50% risk of being affected with the syndrome. The daughters of female carriers are at 50% risk of being carriers themselves. Females may have mild manifestations of the syndrome. The syndrome is caused by mutation in a gene called FGDY1 in band p11.21 on the X chromosome.

Pathophysiology

The Aarskog–Scott syndrome is due to mutation in the FGD1 gene. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates Cdc42, a member of the Rho (Ras homology) family of the p21 GTPases. By activating Cdc42, FGD1 protein stimulates fibroblasts to form filopodia, cytoskeletal elements involved in cellular signaling, adhesion, and migration. Through Cdc42, FGD1 protein also activates the c-Jun N-terminal kinase (JNK) signaling cascade, a pathway that regulates cell growth, apoptosis, and cellular differentiation.

Within the developing mouse skeleton, FGD1 protein is expressed in precartilaginous mesenchymal condensations, the perichondrium and periosteum, proliferating chondrocytes, and osteoblasts. These results suggest that FGD1 signaling may play a role in the biology of several different skeletal cell types including mesenchymal prechondrocytes, chondrocytes, and osteoblasts. The characterization of the spatiotemporal pattern of FGD1 expression in mouse embryos has provided important clues to the understanding of the pathogenesis of Aarskog–Scott syndrome.

It appears likely that the primary defect in Aarskog–Scott syndrome is an abnormality of FGD1/Cdc42 signaling resulting in anomalous embryonic development and abnormal endochondral and intramembranous bone formation.

Diagnosis

Genetic testing may be available for mutations in the FGDY1 gene. Genetic counseling is indicated for individuals or families who may carry this condition, as there are overlapping features with Fetal alcohol syndrome.[1]

Treatment

Surgery may be required to correct some of the anomalies, and orthodontic treatment may be used to correct some of the facial abnormalities. Trials of growth hormone have not been effective to treat short stature in this disorder.

Prognosis

Mild degrees of mental slowness may be present, but affected children usually have good social skills. Some males may exhibit reduced fertility.

Some recent findings have included cystic changes in the brain and generalized seizures[citation needed] . There may be difficulty growing in the first year of life in up to one-third of cases. Misaligned teeth may require orthodontic correction. An undescended testicle will require surgery.

Adenylosuccinate lyase deficiency (MIM 103050, ADSL) is a rare autosomal recessive disease causing severe mental retardation and/or autistic features.1,2 Seizures are often observed (80%),3 varying in age of onset (from newborn to late childhood) and nature (tonic-clonic, “suppression burst” pattern, West syndrome, etc.), and are very often resistant to all medication. Around 50% of the children show autistic-like behaviour.4 Microcephaly is rare (1/13 of reported cases). Non-specific anomalies of the brain, such as hypoplasia of the vermis, cerebral atrophy,5 lack of myelination,6 white matter anomalies,7 and lissencephaly4 have often been described.

Other Complications: • Low self-esteem • Social difficulties related to physical problems • Male infertility in those with both testes undescended • Problems with the structure of the heart • Accumulation of fluid in tissues of body (lymphedema, cystic hygroma) • Failure to thrive in infants.

History

The syndrome is named for Dagfinn Aarskog, a Norwegian pediatrician and human geneticist who first described it in 1970,[2] and for Charles I. Scott, Jr., an American medical geneticist who independently described the syndrome in 1971.[3]

References

^ CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http://www.cdc.gov/fas/faspub.htm